Abstract
The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body Creatine is a carninutrient, which means that it is only available to adults via animal foodstuffs, principally skeletal muscle, or via supplements. Infants receive creatine in mother’s milk or in milk-based formulas. Vegans and infants fed on soy-based formulas receive no dietary creatine. Plasma and muscle creatine levels are usually somewhat lower in vegetarians than in omnivores. Human intake of creatine was probably much higher in Paleolithic times than today; some groups with extreme diets, such as Greenland and Alaskan Inuit, ingest much more than is currently typical. Creatine is synthesized from three amino acids: arginine, glycine and methionine (as S-adenosylmethionine). Humans can synthesize sufficient creatine for normal function unless they have an inborn error in a creatine-synthetic enzyme or a problem with the supply of substrate amino acids. Carnivorous animals, such as lions and wolves, ingest much larger amounts of creatine than humans would. The gastrointestinal tract and the liver are exposed to dietary creatine in higher concentrations before it is assimilated by other tissues. In this regard, our observations that creatine supplementation can prevent hepatic steatosis (Deminice et al. J Nutr 141:1799–1804, 2011) in a rodent model may be a function of the route of dietary assimilation. Creatine supplementation has also been reported to improve the intestinal barrier function of the rodent suffering from inflammatory bowel disease.
Similar content being viewed by others
Abbreviations
- AGAT:
-
Arginine:glycine amidinotransferase
- GAA:
-
Guanidinoacetic acid
- GAMT:
-
Guanidinoacetate methyltransferase
- HIF:
-
Hypoxia inducible transcription factor
- SAM:
-
S-adenosylmethionine
- SLC6A8:
-
Creatine transporter
References
Braissant O (2012) Creatine and guanidinoacetate transport at blood-brain and blood-cerebrospinal fluid barriers. J Inherit Metab Dis 35:655–664
Braissant O, Henry H, Loup M, Eilers B, Bachmann C (2001) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Mol Brain Res 86:193–201
Braissant O, Henry H, Béard E, Uldry J (2011) Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino Acids 40:1315–1324
Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261
Brosnan JT, Brosnan ME (2010) Creatine metabolism and the urea cycle. Mol Genet Metab 100:S49–S52
Brosnan MJ, Chen L, Van Dyke TA, Koretsky AP (1990) Free ADP levels in transgenic mouse liver expressing creatine kinase. Effects of enzyme activity, phosphagen type, and substrate concentration. J Biol Chem 265:20849–20855
Brosnan ME, MacMillan L, Stevens JR, Brosnan JT (2015) Division of labour: how does folate metabolism partition between one-carbon metabolism and amino acid oxidation? Biochem J 472:135–146
Burke DG, Chilibeck PD, Parise G, Candow DG, Mahoney D, Tarnolpolsky M (2003) Effect of creatine and weight training on muscle creatine and performance in vegetarians. Med Sci Sports Exerc 35:1946–1955
Cambero MI, Seuss I, Honikel KO (1992) Flavor compounds of beef broth as affected by cooking temperature. J Food Sci 57:1285–1290
Carducci C, Birarelli M, Leuzzi V, Carducci C, Battini R, Cioni G, Antonozzi I (2002) Guanidinoacetate and creatine plus creatinine assessment in physiologic fluids: and effective diagnostic tool for the biochemical diagnosis of arginine:glycine amidinotransferase and guanidinoacetate methyltransferase deficiencies. Clin Chem 48:1772–1778
Cordain L, Eaton SB, Miller JB, Mann N, Hill K (2002) The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr 56:S42–S52
Cote-Robitaille M-E, Girard CL, Guay F, Matte JJ (2015) Oral supplementation of betaine, choline, creatine and vitamin B6 and their influence on the development of homocysteinaemia in neonatal piglets. J Nutr Sci 4:e31
Crim MC, Calloway DH, Margen S (1975) Creatine metabolism in men: urinary creatine and creatinine excretions with creatine feeding. J Nutr 105:428–438
Da Silva RP, Clow K, Brosnan JT, Brosnan ME (2014a) Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas. Brit J Nutr 111:571–577
Da Silva RP, Kelly KB, Leonard K-A, Jacobs RL (2014b) Creatine reduces hepatic TG accumulation in hepatocytes by stimulating fatty acid oxidation. Biochim Biophys Acta 1841:1639–1646
Deminice R, da Silva RP, Lamarre SG, Brown C, Furey GN, McCarter SA, Jordao AA, Kelly KB, King-Jones K, Jacobs RL, Brosnan ME, Brosnan JT (2011) Creatine supplementation prevents the accumulation of fat in the livers of rats fed a high-fat diet. J Nutr 141:1799–1804
Derave W, Marescau B, vanden Eede E, Eijnde BO, de Deyn P, Hespel P (2004) Plasma guanidino compounds are altered by oral creatine supplementation in healthy humans. J Appl Physiol 97:852–857
Edison EE, Brosnan ME, Aziz K, Brosnan JT (2013) Creatine and guanidinoacetate content of human milk and infant formulas: implications for creatine deficiency syndromes and amino acid metabolism. Brit J Nutr 110:1075–1078
Glover LE, Bowers BE, Saeedi B, Ehrentraut SF, Campbell EL, Bayless AJ, Dobrinskikh E, Kendrick AA, Kelly CJ, Burgess A, Miller L, Kominsky DJ, Jedlicka P, Colgan SP (2013) Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc Natl Acad Sci USA 110:19820–19825
Guthmiller P, Van Pilsum JF, Boen JR, McGuire DM (1994) Cloning and sequencing of rat kidney l-arginine:glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem 269:17556–17560
Hanna-El-Daher L, Béard E, Henry H, Tenenbaum L, Braissant O (2015) Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development. Neurobiol Dis 79:14–27
Harris RC, Lowe JA, Warnes K, Orme CE (1997) The concentration of creatine in meat, offal and commercial dog food. Res Vet Sci 62:58–62
Harris RC, Nevill M, Harris DB, Fallowfield JL, Bogdanis GC, Wise JA (2002) Absorption of creatine supplied as a drink, in meat or in solid form. J Sports Sci 20:147–151
Ho K-J, Mikkelson B, Lewis LA, Feldman SA, Taylor CB (1972) Alaskan Arctic Eskino: responses to a customary high fat diet. Am J Clin Nutr 25:737–745
Ipsiroglu OS, Stromberger C, Ilas J, Hӧger H, Mühl A, Stӧckler-Ipsiroglu S (2001) Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. Life Sci 69:1805–1815
Ivanov AI, Parkos CA, Nusrat A (2010) Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol 177:512–524
Jahangir E, Vita JA, Handy D, Holbrook M, Palmisano J, Beal R, Loscalzo J, Eberhardt RT (2009) The effect of l-arginine and creatine on vascular function and homocysteine metabolism. Vasc Med 14:239–248
Jonquel-Chevalier Curt M, Voicu P-M, Fontaine M, Dessein A-F, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, Vamecq J (2015) Creatine biosynthesis and transport in health and disease. Biochimie 119:146–165
Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM (2015) A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163:643–655
Kuipers RS, Luxwolda MF, Dijck-Brouwer DAJ, Eaton SB, Crawford MA, Cordain L, Muskiet FAJ (2010) Estimated macronutrient and fatty acid intake from an East African Paleolithic diet. Br J Nutr 104:1666–1687
Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M (2011) Disorders of creatine transport and metabolism. Am J Med Genet 157:72–78
McCarty MF (2001) Supplemental creatine may decrease serum homocysteine and abolish the homocysteine “gender gap” by suppressing endogenous creatine synthesis. Med Hypotheses 56:5–7
McGuire DM, Gross MD, Van Pilsum JF, Towle HC (1984) Repression of rat kidney l-arginine:glycine amidinotransferase synthesis by creatine at a pretranslational level. J Biol Chem 259:12034–12038
Mora L, Hernández-Cázares AS, Sentandreu MA, Toldrá F (2010) Creatine and creatinine evolution during the processing of dry-cured ham. Meat Sci 84:384–389
Nabuurs CI, Choe CU, Veltien A, Kan HE, van Loon LJC, Rodenburg RJT, Matschke J, Wieringa B, Kemp GJ, Isbrandt D, Heerschap A (2013) Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake. J Physiol 591:571–592
Nasrallah F, Kraoua I, Curt MJ-C, Bout M-A, Taieb SH, Feki M, Khouja N, Briand G, Kaabachi N (2012) Guanidinoacetate methyltransferase (GAMT) deficiency in two Tunisian siblings: clinical and biochemical features. Clin Lab 58:427–432
Nasrallah F, Benrhouma H, Kraoua I, Briand G, Omar S, Ben Youssef IT, Kaabachi N (2015) Mixed movement disorders revealing an atypical form of creatine deficiency syndrome. Iran J Neurol 14:47–49
Ogawa H, Date T, Gomi T, Konishi K, Pitot HC, Cantoni GL, Fujioka M (1988) Molecular cloning, sequence analysis, and expression in Escherichia coli of the cDNA for guanidinoacetate methyltransferase from rat liver. Proc Natl Acad Sci USA 85:694–698
Pasquali M, Schwarz E, Jensen M, Yuzyuk T, DeBiase I, Randall H, Longo N (2014) Feasibility of newborn screening for guanidinoacetate methyltransferase (GAMT) deficiency. J Inherit Metab Dis 37:231–236
Peters BA, Hall MN, Liu X, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Ilievski V, Graziano JH, Gamble MV (2015) Low-dose creatine supplementation lowers plasma guanidinoacetate, but not plasma homocysteine, in a double-blind, randomized, placebo-controlled trial. J Nutr 145:2245–2252
Petr M, Ŝteffl M, Kohliková E (2013) Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. Physiol Rev 62:721–729
Purchas RW, Rutherfurd SM, Pearce PD, Vather R, Wilkinson BHP (2004) Cooking temperature effects on the forms of iron and levels of several other compounds in beef semitendinosus muscle. Meat Sci 68:201–207
Pyne-Geithman GJ, deGrauw TJ, Cecil KM, Chuck G, Lyons MA, Ishida Y, Clark JF (2004) Presence of normal creatine in the muscle of a patient with a mutation in the creatine transporter: a case study. Mol Cell Biochem 262:35–39
Schulze A, Battini R (2007) Pre-symptomatic treatment of creatine biosynthesis defects. In: Salomons GS, Wyss M (eds) Creatine and creatine kinase in health and disease. Springer, New York
Solis MY, de Salles Painelli V, Artioli G, Roschel H, Otaduy MC, Gualano B (2014) Brain creatine depletion in vegetarians? A cross-sectional 1H-magnetic resonance spectroscopy (1H-MRS) study. Br J Nutr 111:1272–1274
Sotgia S, Carru C, Caria MA, Tadolini B, Deiana L, Zinellu A (2007) Acute variations in homocysteine levels are related to creatine changes induced by physical activity. Clin Nutr 26:444–449
Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 281:E1095–E1100
Steenge GR, Verhoef P, Greenhaff PL (2001) The effect of creatine and resistance training on plasma homocysteine concentration in healthy volunteers. Arch Intern Med 161:1455–1456
Streijger F, Pluk H, Oerlemans F, Beckers G, Bianco AC, Ribiero MO, Wieringa B, Van der Zee CEEM (2009) Mice lacking brain-type creatine kinase activity show defective thermoregulation. Physiol Behav 97:76–86
Sykut-Cegielska J, Gradowska W, Mercimek-Mahmutoglu S, Stӧckler-Ipsiroglu S (2004) Biochemical and clinical characteristics of creatine deficiency syndromes. Acta Biochim Polonica 51:875–882
Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40:1271–1296
Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G (2013) Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 45:463–477
Wu G, Jaeger LA, Bazer FW, Rhoads JM (2004) Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. J Nutr Biochem 15:442–451
Acknowledgments
This work was supported by Grants from the Canadian Institutes of Health Research (RNL 119957) and the Research Development Corporation (5404-1433-101. We thank Dr. Jennifer R. Stevens for assistance with the figures.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical statement
This article is a review summarizing the results and conclusions of published studies on human or animal subjects. All of the work carried out in our laboratories was approved by our local Ethics Committees.
Additional information
Handling Editor: T. Wallimann and R. Harris.
Rights and permissions
About this article
Cite this article
Brosnan, M.E., Brosnan, J.T. The role of dietary creatine. Amino Acids 48, 1785–1791 (2016). https://doi.org/10.1007/s00726-016-2188-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-016-2188-1